The overall objectives of this research project are: (1) determination of the cell type which expresses the Ir-1 gene product; (2) genetic mapping of immune response genes with respect to the H-2 locus; (3) attempts to characterize and isolate the Ir-1 gene product; (4) search for histocompatibility-linked immune response genes associated with susceptibility or resistance to infectious, neoplastic, and autoimmune diseases. For the study of these four problems, the following experimental approaches are used: (1) the development of an in vitro secondary, and hopefully primary, antibody-forming system in which immunized or normal lymphocytes from high responder and low responder mice can be stimulated with (T,G)-A--L, (H,G)-A--L, and (Phe,G)-A--L in vitro. Once such a system has been developed, the role of hapten-specific B cells and carrier-specific T cells will be analyzed using (T,G)-A--L as the immunogen and the stimulus for the production of specific antibodies, as well as DNP-(T,G)-A--L as the immunogen, in which case (T,G)-A--L will function as the carrier and DNP as the hapten. The inhibitory effect of anti-Ig, anti-H-2K, anti-H-2D, and anti-Ia antisera will be studied. We hope to pinpoint the expression of Ir genes in T cells. In vivo experiments on the interaction of T and B cells in the immune response to (T,G)-A--L, when these cells differ for a major histocompatibility complex, will also be studied. (2) Mapping studies on natural antigens, such as ovomucoid and BGG, and on synthetic antigens of specified sequence. The latter will be used to elucidate the structure of the antigenic determinant recognized in Ir-l regulated immune reactions. (3) Attempts will be made to isolate T antigen binding cells for (T,G)-A--L. Once this has been done, a variety of techniques will be used to attempt to produce anti-T-cell receptor antibody. (4) We are continuing to develop the necessary cell lines and congenic inbred strains for the study of Rav-1, and H-2-linked murine virus-leukemia resistance gene. The possible role of Ir-l in the Rgv-l effect will be studied. Similar studies will be carried out on the genetic control of susceptibility to murine lymphocytic choriomeningitis.